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Definition/Description

Chemotherapy is the use of medicines or drugs to treat a disease, such as cancer. This treatment is often referred to as “chemo.” Two other medical terms used to describe cancer chemotherapy are antineoplastic (meaning anti-cancer) therapy and cytotoxic (cell-killing) therapy. Chemotherapy differs from surgery and radiation due to the fact that it’s a systemic treatment. This means the drugs travel throughout the body to reach cancer cells wherever they are.[1] During this process, the nonspecific chemotherapeutic agents not only target the cancer cells but also affect normal cells. Chemo can kill cancer cells that have metastasized or spread to parts of the body far away from the primary tumor.[2] It is used to treat about 60% of metastatic cancers that cannot be cured by localized methods.[3]

The first drug used for cancer chemotherapy did not start out as a medicine. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. Doctors then reasoned that something in the gas damaged the rapidly growing white blood cells therefore it could have a similar effect on cancer. So, in the 1940s, several patients with advanced lymphomas were given the drug intravenously, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed.[1]

Prevalence

[4] Systemic chemotherapy plays a major role in the management of the 60% of malignancies that are not curable by regional modalities. [5] It can significantly delay and interfere with cancer treatment because the presence of chemotherapy-induced side effects can warrant a dose reduction, or a delay or cessation in treatment. [6]

More information about most prevalent chemotherapy side effects in detail:

Chemo-induced Peripheral Neuropathy (CIPN): It is estimated that the prevalence of peripheral neuropathy is 3-7% in patients with single chemotherapy agents and around 38% in patients with multiple chemotherapy agents. However it is difficulty to be certain about the prevalence due to a lack of diagnostic criteria and a standard mechanism of measuring and reporting. Much research about treatment for CIPN is derived from studies for the treatment of diabetic neuropathy and HIV-induced neuropathy. The most common chemotherapy agents that cause peripheral neuropathy are platinum compounds, taxanes, vinca alkaloids, thalidomide, and bortezomib[6]

"Chemo-brain": Affects about 1/3 of patients. It is associated more with higher dosages of chemotherapy agents. Treatment to prevent or reverse "chemo-brain" includes reorganizing home and work environment, memorization exercises, the use of mnemonic devices, notes, avoidance of distractions, and possibly medications[7]

Associated Co-morbidities

The most common pre-existing condition observed in all patients with cancer is hypertension. Diabetes is the second most prevalent pre-existing condition in middle-aged patients, however a previous solid tumor is the second most common pre-existing condition in patients 74 years of age or older.

Chemotherapy Agents

Alkylating agents: These directly damage DNA to prevent the cancer cell from reproducing. These agents work in all phases of the cell cycle. Alkylating agents commonly treat leukemia, lymphoma, Hodgkin disease, multiple myeloma, sarcoma, and cancers of the lung, breast, and ovary. Because these drugs damage DNA, they can cause long-term damage to the bone marrow. There are different classes of alkylating agents, including: Oxaliplatin, Nitrogen mustards, Nitrosoureas, Alkyl Sulfonates, Triazines, and Ethylenimines.

Antimetabolites: This is a class of drugs that interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. They are commonly used to treat leukemias, breast and ovary cancers. Examples include: Capecitabine, Cladribine, Clofarabine, Cytarabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Methotrexate, Pemetrexed, Pentostatin, and Thioguanine.

Anthracyclines: These anti-tumor antibiotics interfere with enzymes involved in DNA replication and are used for a variety of cancers. These drugs work in all phases of the cell cycle. A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses. Because of this, lifetime dose limits are often placed on these drugs. Examples include: Daunorubicin, Doxorubicin, Epirubicin and Idarubicin.

Mitoxantrone: This anti-tumor antibiotic also interferes with enzymes involved in DNA replication. This drug also has potential for damaging the heart and can lead to treatment-related leukemia. Mitoxantrone is used to treat prostate cancer, breast cancer, lymphoma, and leukemia.

Topoisomerase inhibitors: These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied. They are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers. Examples include: Topotecan, Airinotecan, Etoposide and Teniposide.

Mitotic inhibitors: These medications are often plant alkaloids and other compounds derived from natural products. They can stop mitosis or inhibit enzymes from making proteins needed for cell reproduction. They are used for breast and lung cancer, myelomas, lymphomas, and leukemias. These drugs are known for their potential to cause peripheral nerve damage. Examples include: Taxanes, Epothilones, Vinca alkaloids, and Estramustine.

Corticosteroids: Steroids are hormone-like drugs that are useful in treating cancer including lymphoma, leukemias, and multiple myeloma. Corticosteroids are also commonly used as anti-emetics to help prevent nausea and vomiting caused by chemotherapy. They are also used before chemotherapy to help prevent severe allergic reactions. When a corticosteroid is used to prevent vomiting or allergic reactions, it’s not considered chemotherapy. Examples include: Prednisone, Methylprednisolone, and Dexamethasone.

Chemoprotectants: Designed to reduce toxicity of chemotherapy drugs and repair DNA while not reducing the effectiveness of the chemotherapy drug. Amofistine is the most common medication. Studies have investigated its effect on taxanes and pathlitaxel and have shown that amofistine has no effect on sensory and motor neurotoxic symptoms. Leukovorin is another drug designed to counteract the effects of the chemotherapy drug methotrexate.

Vitamins and Minerals:

Vitamin E - Vitamin E is an antioxidant and is used to protect against several side effects of cisplatin and cytotoxic drugs such as numbness, tingling, burning, or pain. Research studies show Vitamin E decreases these neurotoxic symptoms.

Calcium and Magnesium Infusions - Designed to prevent neurotoxicity side effects associated with oxaliplatin. Studies have shown that they effectively reduce pseudolaryngospasm, neuropathy and other neurotoxic symptoms.

Anticonvulsants: Carbamazepine most common. Small studies have shown that it decreases or eliminates CIPN.

Glutamine: Used to treat symptoms of paclitaxel. Research shows that glutamine reduces side effects of chemotherapy, particularly dysesthesias in the fingers and toes, weakness, and loss of vibratory sensation.

Glutathione: Used to treat symptoms of platinum compounds. Shown through research to reduce CIPN. It has also been shown to improve mood and decrease depression. However a side effect of glutathione is weight gain.

Capsaicin ointment: Found to significantly decrease hypoesthesia from diabetic neuropathy. May cause allergic reaction in a small percentage of people. It's effects on CIPN have not been studied.

Chinese Herbal Medicines: Low level evidence that these medicines reduce nausea and vomiting and improve leukopenia and immune system function.[9]

Diagnostic Tests/Lab Tests/Lab Values

Complete Blood Counts (CBCs)[3] are routinely performed during chemotherapy to check the number of each type of blood cell circulating in the body.

This diagnostic test was designed to determine an individual’s risk of developing side effects associated with chemotherapy based on their genomic profile. The preliminary results of a clinical study of OnPART were reported by the company at the annual meeting of the Multinational Association of Supportive Care in Cancer. In this study, OnPART correctly identified patients at risk for chemotherapy-induced diarrhea (CID) with an accuracy of 96.7%. A larger study confirmed these findings and allowed the first phase of development to be completed. Further development and testing is currently underway.[7][10]

Etiology/Causes

Cancerous cells are marked by uncontrolled division and mitosis where they no longer stop dividing in response to the normal checks and balances in place within the human body to stop cell division. Chemotherapy agents are designed kill these cells by targeting cells that rapidly divide. Unfortunately there are several types of healthy cells that rapidly divide, and chemotherapy agents destroy these too. The most commonly affected healthy cells are in the bone marrow, mouth, GI tract, and hair follicles. This results in many GI complications, mouth sores, hair loss, and low blood cell counts. Side effects of chemotherapy agents result from other causes too. For example, CIPN is caused by the inactivation of necessary metabolic components of motor, sensory, and autonomic axons by neurotoxic chemotherapy agents. The causes of some other side effects, such as "chemo brain" remain unknown.[13]

Systemic Involvement

Respiratory SystemPatients receiving chemotherapy are at risk for developing infection, metastatic disease, pulmonary embolism, or drug-induced pulmonary toxicity. Chemo drugs commonly cause pulmonary toxicity but many other drugs may also have an association. Initial presentation can be hard to detect because the patient may be asymptomatic and changes on chest X-ray may be minimal. However, patients may complain of a dry cough or increasing breathlessness with exercise. Due to the immunosuppressant effects of chemotherapy drugs, patients may also present with infections such as pneumonia.

Cardiovascular SystemCardiac toxicity due to chemotherapy is common and may be life threatening or cause significant morbidities. Common symptoms include hypotension, hypertension, arrhythmias, myocardial infarction, congestive cardiac failure, cardiomyopathy, myocarditis, and pericarditis, leading to pericardial effusion and cardiac tamponade. Cardiac toxicity can be immediate or delayed after completion of the course of chemotherapy.

Chemotherapy drugs tend to damage myocytes, cardiac valves, vessels and the pericardium. Risk factors for cardiotoxicity include pre-existing cardiac disease, the use of concurrent chemotherapy agents, older than the age of 70, female, and current or previous radiation therapy involving the mediastinum.

Nervous SystemChemotherapy can damage any part of the nervous system. Chemotherapy agents can cause neurotoxicity, peripheral neuropathy, muscle pain, cranial neuropathy, seizures or exacerbate pre-existing neurological conditions. There are also effects on the autonomic nervous system, which can cause orthostatic hypotension. In high-doses some drugs may induce acute encephalopathy, causing confusion, seizures, hemiparesis, and coma. It is important that physical therapists conduct a full neurological examination to detect any neurological damage.

GastrointestinalGastrointestinal toxicity is a common side effect of most chemotherapy drugs. Signs and symptoms of gastrointestinal toxicity includes: nausea and vomiting, mucositis, diarrhea and dehydration. It is important that fluid and electrolytes are replenished before and after exercise.[14]

Medical Management (Current Best Evidence)

Dosage

Depending on the drug given, there are different ways to determine chemotherapy doses. The overall dose may be based on a person’s body weight or can be determined based on body surface area, which is calculated using the patient’s height and weight.

Dosage considerations include:

Age

Nutritional status

BMI

Previous or current medications

Previous or current radiation therapy

Blood cell count

Liver and kidney function

Cycle

Chemotherapy is generally given at regular intervals called cycles. A chemotherapy cycle may involve a dose of one or more drugs followed by several days or weeks without treatment. This gives normal cells time to recover from the drug’s side effects. Sometimes, doses may be given several days in a row, or every other day for several days, followed by a period of rest. Some drugs work best when given continuously over a set number of days.

Cycle considerations include:

Minimizing side effects

Number of drugs being used

Type of cancer

Stage of cancer

Health status

Goals of treatment

It's important, when possible, to get the full course of chemotherapy and to keep the cycles on schedule. This will give you the best chance to get the maximum benefit from treatment.[1]

Physical Therapy Management (Current Best Evidence)

It is extremely important to take a client history of current chemotherapy dosages and to monitor the hematologic values in clients receiving physical therapy. Current guidelines recommend that individuals undergoing chemotherapy should not exercise within two hours of their treatment because the increase in blood circulation during exercise may change the effects of the chemotherapy treatment. The suggested two hour delay is reasonable given the half-life of most chemotherapeutic agents.

Exercise Precautions for the Current Cancer Patient[3](Box 9-5 from Pathology: Implications for the Physical Therapist)

Fever

Extreme or unsual fatigue

Unusual muscular weakness

Irregular heart beat, chest palpitations, chest pain

Sudden onset of dyspnea

Leg pain or cramps

Unusual joint pain

Recent or new-onset back, neck, or bone pain

Unusual bruising, nosebleeds, or bleeding from any other body opening

Sudden onset of nausea during exercise

Rapid weight gain or weight loss

Severe diarrhea or vomiting

Disorientation, confusion, dizziness, or lightheadedness

Blurred vision or other visual disturbances

Skin pallor or unusual skin rash

Contact physician about any of these symptoms.

Specific Exercise Precautions for the Cancer Survivor Post-treatment[3](Box 9-6 from Pathology: Implications for the Physical Therapist)

Severe anemia, medical eval necessary

Compromised immune function / bone marrow transplantation; Should avoid public gyms for about 1 year

Stationary bike may be better than treadmill for patients with poor balance, gait disturbances, or peripheral neuropathies

Physical Therapy Implications

Strength:

Research has shown that resistance training has been shown to improve strength in people with neuropathy from causes other than chemotherapy. Some moderate-level studies have also shown that resistance training may reverse muscle atrophy caused from peripheral neuropathy.[6]

Pain and Sensation:

Pain and sensation deficits were shown to be effectively treated by long-wave diathermy and interferential currents after long periods of treatment (>30 weeks).[15]

TENS is shown to improve numbness, lancinating pain, allodynia, prickling sensations, and allodynia in people with diabetic neuropathy but the effects on CIPN haven't been studied.[6]

High frequency muscle stimulation has also been shown to improve diabetic neuropathy symptoms such as numbness, burning, paresthesia, and dysesthesia. In one study it was shown to reduce pain more than TENS. However these improvements only lasts a few days. It has not been studied in people with CIPN.[6]

Balance:

Jung et al. described the use of Yoga and balance training as valid exercise suggestions for CIPN.[15]

Endurance:

According to a study by Dimeo et al, a six week endurance training program of low to moderate levels of aerobic exercise showed significant improvements in physical performance and temperament while reducing mental stress and fatigue when undergoing chemotherapy. [5]

F. Kwiatkowski et al. included walking over a flat ground or pedal on a cycloergometer as well as aquanastics (water exercises) to improve cardiovascular fitness following chemotherapy.[16]

Range of motion:

Stretching exercises have also been shown to improve functional reach in people with peripheral neuropathy.[6]

Physical therapy treatment can consist of a warm up, and recovery through neuroproprioceptive facilitation (PNF) in order to improve muscle tone and postural stability which can improve proprioception for the patient with CIPN. [17]

- activities for developing coordination: adapted ball game with coordination of visual and kinesthetic aspects for LEs [17]

Quality of life

Physical therapy treatment has been incorporated into a 12 month study by for breast cancer survivors to increase QOL. Jung et al. suggests Reiki ( a Japanese stress reducing technique) to decrease pain and improve QOL of the CIPN patient. [15]

Assistive Devices

There are no research studies about the use of assistive devices with patients with cancer. However there are some for the effects of a cane and orthotic for patients with diabetic neuropathy. These patients found that the cane and orthotic helped with injury prevention. They were not found to have an effect on the peripheral neuropathy. Patients with cancer are often referred to physical therapy to be fitted with an assistive device, orthotic, or splint to improve balance and proper alignment of the lower extremity.[6]

Other Management Strategies (Current Best Evidence)

Acupuncture: Studies show acupuncture may be helpful in relieving nausea and may also help relieve certain types of pain in people receiving chemotherapy. Also shown to improve gait and balance, as well as decrease the required dosage of analgesic drugs. In one study, these improvements were sustained for 6 months and no adverse effects were seen. Not shown to have an effect on neuropathy or vibration sensation.

Aromatherapy: Aromatherapy uses fragrant oils to provide a calming sensation which may be helpful in relieving nausea, pain and stress.

Biofeedback: Biofeedback may be helpful in relieving pain in people with cancer.

Behavioral Therapy: Systemic desensitization has been found to significantly decrease anticipatory N&V before chemotherapy treatments.[18]

Exercise: Exercise may help you manage signs and symptoms during and after cancer treatment. Gentle exercise, such as walking or swimming, may help relieve fatigue and stress and help you sleep better.

Hypnosis: Hypnosis may be helpful for people with cancer who are experiencing anxiety, pain and stress. It may also help prevent anticipatory nausea and vomiting that can occur if chemotherapy has made you sick in the past.

Massage therapy: Studies have found massage can be helpful in relieving pain in people with cancer. It may also help relieve anxiety, fatigue and stress.

Meditation: Meditation may help people with cancer by relieving anxiety and stress.

Music therapy: Music therapy may help relieve pain and control nausea and vomiting.

Pulsed Infrared Light Therapy: Also called anodyne therapy. Machine delivers infrared light to foot with neuropathy (CIPN has not been studied but other forms of neuropathy have) and stimulates nitric oxide production to improve circulation. Shown to improve sensation, neuropathic symptoms and pain in most patients, excluding those with very advanced neuropathy scores.[6]

Relaxation techniques: Relaxation techniques may be helpful in relieving anxiety and fatigue and they may also help people with cancer sleep better.

Spinal Cord Stimulation: Not yet recommended for practice due to lack of research and high surgical risks and costs. The surgery involves placing electric leads into the involved section of the spinal cord or nerve roots to transmit energy that blocks the pain through the gate-control theory. One case study of 2 patients who underwent the surgery showed that they had improved pain, sensation, gait, and flexibility afterwards. They were also able to decrease their analgesic dosage.[6]

Tai chi: Practicing tai chi may help relieve stress.

Yoga: Yoga may provide some stress relief for people with cancer. Yoga has also been shown to improve sleep and reduce fatigue.

Some alternative treatments have been shown to work well together but more research is needed for conclusive evidence. [19]

- May cause similar symptoms such as constipation, diarrhea, nausea and vomitting.

Sample Case Study

Virgil is a 67 year old male who was diagnosed with stage three colon cancer about two years ago. He previously was a school teacher but has recently retired in order to take care of his health. Shortly after being diagnosed he was scheduled for a partial colectomy to remove the affected part of the colon. He continued with chemotherapy, taking capecitabine, orally, twice a day, to increase his likelihood of remaining cancer free. He has been noticing trouble with his balance as well as numbness and tingling in his feet and legs that have resulted in two recent falls. He also has increased occurrence of nausea for the last several months resulting in an overall feeling of fatigue. The patient had some physical therapy services while receiving treatment at the hospital but has not been to see anyone following d/c.

The patient states, “ I want to improve my sensation and balance as well as increase his endurance to more effectively participate in his life.

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